Why is the efficacy of Lorqess so maligned & so misunderstood?
Before Qnexa produced a larger degree of mean weight loss, the Lorqess results would have appeared right in line with all other recent approvals & candidates. So why, all of a sudden, is this degree of mean weight loss no longer acceptable?
The answer to me is obvious, with Qnexa being the elephant in the room. Clearly, the bias in favor of Qnexa is pervasive in the FDA. This has completely muddled their thinking and is undermining their mission of providing safe & effective drugs for the American people.
The FDA has two alternative guidelines for demonstrating efficacy in a weight loss agent. The first is easy & intuitive to understand: the drug produces at least 5% more mean weight loss than placebo. This is the criterion that Qnexa has met, at least with its higher dosages. (Importantly, phentermine is the only currently approved drug that meets this standard- and phentermine is one of the two constituents of Qnexa.) The second criteria is difficult to explain & understand, so its achievement does not get the media excited. However, it is valid, and it serves to demonstrate efficacy when a drug tends to produce very different results with different subgroups of the study population. To put it simply, lorcaserin does not work very well for about a third of the population. It works moderately well (about 5% weight loss) for about another third. But it works extremely well for one-third of all obese individuals. (The one-third number includes all of the study participants, including those who dropped out.) Out of the study population that completed one full year on lorcaserin, 66% lost an average of 26 pounds. The top one-quarter of “completers” lost 35 pounds.
Qnexa is an Emperor with no clothes. Qnexa brings absolutely nothing new to the arsenal of weapons currently available to doctors to help their obese patients. Topiramate & phentermine are already freely available and inexpensive. Bariatric doctors already use the combination. Phentermine is restricted to 12 weeks usage for a reason, but can be combined with anything to increase weight loss.
There's no real "magic" in VVUS' magic pill – the trick is phentermine combined with another (very dangerous) anorexigen. Everyone is distracted by CEO Willy's legerdemain - "Watch me pull 37 lbs out of the fat person!" He mis-directed everyone’s attention to the dazzling completer numbers (37 pounds). This is not to minimize Qnexa’s genuine achievement of the FDA first criterion with ITT-LOCF numbers -- but media reports always emphasize the misleading completer statistics (37 pounds sounds so BIG); while the same reports always emphasize lorcaserin’s ITT-LOCF numbers (they sound so small). No doubt about it -- Vivus won the "spin" war. But someone has to acknowledge the facts of the situation.
It is crucial to consider that the new norm for weight loss control may depend on using a combination/cocktail of medications. That is all Qnexa essentially is. It is wrong-headed to expect a single individual agent to produce an equivalent amount of weight loss. In addition, the only currently available single agent that would meet the FDA’s first criterion for efficacy is phentermine. The only fair comparison to Qnexa, which remains to be tested, would be a combination of Lorqess with phentermine: which could be expected to produce similar efficacy with a much better safety profile.
However, if the FDA disapproves Lorqess based on insufficient efficacy, that comparison cannot be made. The FDA may argue that Arena is free to develop new trials to demonstrate the efficacy & safety of “Lor-Phen,” but that is a specious statement. Arena Pharmaceuticals, as a tiny biotech which has already spent hundreds of millions of dollars, and going on 2 decades of research, will be unable to muster the resources or survive as a company. A conspiracy-minded person might conclude that this is deliberate on the part of the FDA, due to the improper & disproportionate influence of Big Pharma with that agency. An Arena bankruptcy would allow a Big Pharma to swoop in & buy Arena’s ground-breaking research at fire-sale prices – they have the resources to finish the necessary trials, & would reap all the reward in this lucrative market.
It is worth noting that Arena asked the FDA about running trials with lorcaserin combined with phentermine, but was discouraged in doing so by the FDA. This could be considered a sensible procedure, to test out lorcaserin first on its own. However, this discouragement takes on a different & more suspicious motivation when you look at the insistent FDA campaign to “dis-qualify” lorcaserin based on insufficient efficacy.
Qnexa, on the other hand, was not even held to the sensible guidance the FDA provides in its own manual. A combination weight loss agent is required to be compared to its constituent components, & to be significantly better in terms of both efficacy & safety. Although Qnexa produced about 3% more weight loss than phentermine or topiramate alone, it did not meet the FDA preferred guidance of being at least twice as effective. That might be excusable if the safety profile met guidance, but the situation is quite the opposite. The FDA states that a combination drug should "exhibit a potentially meaningful improvement in the safety profile compared to the individual components." Not only does Qnexa fail to do that, but it demonstrably compounds the worst safety risks commonly associated with its constituent drugs.
Consider Qnexa’s first Phase III trial, which was the only such trial to compare Qnexa mid- and high- doses to their constituent agents, with these results:
Percentage of Adverse Events in OB-301, by treatment category.
Nervous system disorders
PLACEBO 24.8%
PHEN 7.5 22.0%
TOP 46 38.7%
Q MID 40.6%
PHEN 15 20.4%
TOP 36.4%
Q HIGH 49.1%
Psychiatric disorders
PLACEBO 13.8%
PHEN 7.5 10.1%
TOP 46 17.0%
Q MID 17.0%
PHEN 15 15.7%
TOP 92 17.8%
Q HIGH 25.0
Cardiac disorders
PLACEBO 0.9%
PHEN 7.5 1.8%
TOP 46 1.9%
Q MID 2.8%
PHEN 15 0.0%
TOP 92 0.9%
Q HIGH 6.5%
Adverse Events as Main Reason for Discontinuation of Study Drug:
PLACEBO 7.3%
PHEN 7.5 9.2%
TOP 46 7.4%
Q MID 15%
PHEN 15 10.2%
TOP 92 16.8%
Q HIGH 21.3%
These results speak, I think, for themselves.
Lorcaserin does what Qnexa could never do: it provides a totally new option for doctors trying to help their patients. It is, as claimed, mild & tolerable, with no major safety risks. Once proven out, it can be tested with phentermine to obtain the same excellent efficacy results as Qnexa-- but the substitution of Lorqess for topirimate would be much safer (topiramate was the main "driver" for Qnexa's adverse effects).
The FDA specifically directed the Advisory Committee "We want you to focus on mean weight loss." Why, when their guidance provides categorial efficacy as an equally valid measure of effectiveness? Why is this important option in jeopardy of being denied to potentially millions of people who would benefit from it hugely? Not to mention the huge savings in the health care costs that are projected to result from the “dia-besity” epidemic.
Any risk associated with lorcaserin, or any weight loss drug, is ameliorated by the natural course of events. If the patient does not lose weight, she soon stops taking it. No risk. If the patient has intolerable side-effects, she stops taking it. No risk. If a patient does lose weight, then any possible risk is out-balanced by the many documented benefits of weight loss. Most importantly & particularly, risk of breast cancer has been shown to be reduced by 65% in younger women who are at most risk (as evidenced by genetic markers), if they lose about 10 pounds
http://www.ncbi.nlm.nih.gov/pubmed/16168130
